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Immunoglobulin E

Immunoglobulin E

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Immunoglobulin E is a class of antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...

 (or immunoglobulin "isotype
Isotype (immunology)
An isotype usually refers to any related proteins/genes from a particular gene family. In immunology, the "immunoglobulin isotype" refers to the genetic variations or differences in the constant regions of the heavy and light chains...

") that has been found only in mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...

s. IgE is a monomeric antibody with 4 Ig-like domains (CH1->CH4). It plays an important role in allergy
Allergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...

, and is especially associated with type 1 hypersensitivity
Hypersensitivity
Hypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...

.
IgE has also been implicated in immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...

 responses to most parasitic worm
Parasitic worm
Parasitic worms or helminths are a division of eukaryoticparasites that, unlike external parasites such as lice and fleas, live inside their host. They are worm-like organisms that live and feed off living hosts, receiving nourishment and protection while disrupting their hosts' nutrient...

s like Schistosoma mansoni
Schistosoma mansoni
Schistosoma mansoni is a significant parasite of humans, a trematode that is one of the major agents of the disease schistosomiasis. The schistosomiasis caused by Schistosoma mansoni is intestinal schistosomiasis....

, Trichinella spiralis
Trichinella spiralis
Trichinella spiralis is a nematode parasite, occurring in rats, pigs, bears and humans, and is responsible for the disease trichinosis. It is sometimes referred to as the "pork worm" due to it being found commonly in undercooked pork products...

, and Fasciola hepatica
Fasciola hepatica
Fasciola hepatica, also known as the common liver fluke or sheep liver fluke, is a parasitic flatworm of the class Trematoda, phylum Platyhelminthes that infects the livers of various mammals, including humans. The disease caused by the fluke is called fascioliasis . F...

, and may be important during immune defense against certain protozoa
Protozoa
Protozoa are a diverse group of single-cells eukaryotic organisms, many of which are motile. Throughout history, protozoa have been defined as single-cell protists with animal-like behavior, e.g., movement...

n parasites such as Plasmodium falciparum
Plasmodium falciparum
Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...

.

Although IgE is typically the least abundant isotype - blood serum
Blood serum
In blood, the serum is the component that is neither a blood cell nor a clotting factor; it is the blood plasma with the fibrinogens removed...

 IgE levels in a normal ("non-atopic") individual are only 0.05% of the Ig concentration, compared to 10 mg/ml for the IgGs (the isotypes responsible for most of the classical adaptive immune response) - it is capable of triggering the most powerful immune reactions.

IgE was discovered in 1966 by the Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...

ese scientist couple Teruko and Kimishige Ishizaka
Kimishige Ishizaka
Dr is a Japanese scientist who discovered the antibody class IgE in 1966. His work has been regarded as a major breakthrough in the understanding of allergy. He was awarded the 1973 Gairdner Foundation International Award and the 2000 Japan Prize for his work in immunology. He was elected a member...

.

Receptors


IgE elicits an immune response by binding to Fc receptor
Fc receptor
An Fc receptor is a protein found on the surface of certain cells - including natural killer cells, macrophages, neutrophils, and mast cells - that contribute to the protective functions of the immune system....

s found on the surface of mast cell
Mast cell
A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin...

s and basophils, and are also found on eosinophils, monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...

s, macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...

s and platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes.  The average lifespan of a platelet is normally just 5 to 9 days...

s in humans. Fcε has two types:
  • FcεRI, the high-affinity IgE receptor
  • FcεRII, also known as CD23, is the low-affinity IgE receptor


IgE can upregulate the expression of both Fcε receptors. FcεRI is expressed only on mast cells
Mast cell
A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin...

 and/or basophils
Basophil granulocyte
Basophil granulocytes, sometimes referred to as basophils, are the least common of the granulocytes, representing about 0.01% to 0.3% of circulating white blood cells....

 in both mice and humans. Aggregation of antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...

s and binding of IgE to the FcεRI on mast cells causes degranulation
Degranulation
Degranulation is a cellular process that releases antimicrobial cytotoxic molecules from secretory vesicles called granules found inside some cells...

 and the release of mediators from the cells, while basophils cross-linked with IgE release type 2 cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

s like interleukin-4 (IL-4) and interleukin-13 (IL-13) and other inflammatory mediators. The low-affinity receptor (FcεRII) is always expressed on B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...

s, but its expression can be induced on the surfaces of macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...

s, eosinophils, platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes.  The average lifespan of a platelet is normally just 5 to 9 days...

s, and some T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...

s by IL-4.

Physiology


There is much speculation into what physiological benefits IgE contributes, and, so far, circumstantial evidence in animal models and statistical population trends have hinted that IgE may be beneficial in fighting gut parasites
Parasitism
Parasitism is a type of symbiotic relationship between organisms of different species where one organism, the parasite, benefits at the expense of the other, the host. Traditionally parasite referred to organisms with lifestages that needed more than one host . These are now called macroparasites...

 such as Schistosoma mansoni
Schistosoma mansoni
Schistosoma mansoni is a significant parasite of humans, a trematode that is one of the major agents of the disease schistosomiasis. The schistosomiasis caused by Schistosoma mansoni is intestinal schistosomiasis....

, but this has not been conclusively proven in humans.

Although it is not yet well understood, IgE may play an important role in the immune system’s recognition of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

, in which the stimulation of a strong cytotoxic response against cells displaying only small amounts of early cancer markers would be beneficial. Of course, if this were the case, anti-IgE treatments such as omalizumab
Omalizumab
Omalizumab is a humanized antibody drug approved for patients with moderate-to-severe or severe allergic asthma, which is caused by hypersensitivity reactions to certain harmless environmental substances...

 might have some undesirable side effects.

Role in disease


Atopic individuals can have up to 10 times the normal level of IgE in their blood (as do sufferers of hyper-IgE syndrome
Hyper-IgE syndrome
Hyperimmunoglobulin E syndrome , also called Job's syndrome and Buckley syndrome, is a heterogeneous group of immune disorders.-Presentation:...

). However, this may not be a requirement for symptoms to occur as has been seen in asthmatics with normal IgE levels in their blood - recent research has shown that IgE production can occur locally in the nasal mucosa.

IgE that can specifically recognise an "allergen" (typically this is a protein, such as dust mite DerP1, cat FelD1, grass or ragweed
Ragweed
Ragweeds are flowering plants in the genus Ambrosia in the sunflower family Asteraceae. Common names include bitterweeds and bloodweeds....

 pollen, etc.) has a unique long-lived interaction with its high-affinity receptor
Biochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes...

 FcεRI so that basophils and mast cells, capable of mediating inflammatory reactions, become "primed", ready to release chemicals like histamine
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...

, leukotriene
Leukotriene
Leukotrienes are fatty signaling molecules. They were first found in leukocytes . One of their roles is to trigger contractions in the smooth muscles lining the trachea; their overproduction is a major cause of inflammation in asthma and allergic rhinitis...

s, and certain interleukins, which cause many of the symptoms we associate with allergy, such as airway constriction in asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...

, local inflammation in eczema
Eczema
Eczema is a form of dermatitis, or inflammation of the epidermis . In England, an estimated 5.7 million or about one in every nine people have been diagnosed with the disease by a clinician at some point in their lives.The term eczema is broadly applied to a range of persistent skin conditions...

, increased mucus
Mucus
In vertebrates, mucus is a slippery secretion produced by, and covering, mucous membranes. Mucous fluid is typically produced from mucous cells found in mucous glands. Mucous cells secrete products that are rich in glycoproteins and water. Mucous fluid may also originate from mixed glands, which...

 secretion in allergic rhinitis
Allergic rhinitis
Allergic rhinitis, also known as pollenosis or hay fever, is an allergic inflammation of the nasal airways.It occurs when an allergen, such as pollen, dust or animal dander is inhaled by an individual with a sensitized immune system...

, and increased vascular permeability, it is presumed, to allow other immune cells to gain access to tissues, but which can lead to a potentially fatal drop in blood pressure as in anaphylaxis
Anaphylaxis
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...

. Although the mechanisms of each response are fairly well understood, why some allergics develop such drastic sensitivities when others merely get a runny nose is still one of science's hot topics. Regulation of IgE levels through control of B cell differentiation to antibody-secreting plasma cells is thought to involve the "low-affinity" receptor FcεRII, or CD23
CD23
CD23, also known as Fc epsilon RII, or FcεRII, is the "low-affinity" receptor for IgE, an antibody isotype involved in allergy and resistance to parasites, and is important in regulation of IgE levels. Unlike many of the antibody receptors, CD23 is a C-type lectin...

. CD23
CD23
CD23, also known as Fc epsilon RII, or FcεRII, is the "low-affinity" receptor for IgE, an antibody isotype involved in allergy and resistance to parasites, and is important in regulation of IgE levels. Unlike many of the antibody receptors, CD23 is a C-type lectin...

 may also allow facilitated antigen presentation, an IgE-dependent mechanism whereby B cells expressing CD23
CD23
CD23, also known as Fc epsilon RII, or FcεRII, is the "low-affinity" receptor for IgE, an antibody isotype involved in allergy and resistance to parasites, and is important in regulation of IgE levels. Unlike many of the antibody receptors, CD23 is a C-type lectin...

 are able to present allergen to (and stimulate) specific T helper cells, causing the perpetuation of a Th2 response, one of the hallmarks of which is the production of more antibodies.

Pharmacology


IgE may be an important target in treatments for allergy and asthma.

Currently, severe allergy and asthma is usually treated with drugs (like anti-histamines) that damp down the late stages of inflammation and relax airway smooth muscle. However, these treatments are fairly broad in their action, so many have unpleasant side-effects; they may also inhibit important protective responses.

In 2002, researchers at The Randall Division of Cell and Molecular Biophysics
Randall Division of Cell and Molecular Biophysics
The Randall Division of Cell and Molecular Biophysics is part of King's College London and one of Britain's research institutions - a centre for study in allergy and asthma; muscle signalling and development; structural biology; muscle biophysics; cell motility and cytoskeleton, and cell...

 determined the structure of IgE. Understanding of this structure (which is atypical of other isotypes in that it is highly bent and asymmetric) and of the interaction of IgE with receptor FcεRI will enable development of a new generation of allergy drugs that seek to interfere with the IgE-receptor interaction. A new treatment, omalizumab
Omalizumab
Omalizumab is a humanized antibody drug approved for patients with moderate-to-severe or severe allergic asthma, which is caused by hypersensitivity reactions to certain harmless environmental substances...

, a monoclonal antibody, recognises IgE not bound to its receptor and is used to neutralise or mop-up existing IgE and prevent it from binding to cells. It may be possible to design treatments cheaper than monoclonal antibodies (for instance, small molecule drugs) that use a similar approach to inhibit binding of IgE to its receptor.

In 1975, Robert N. Hamburger, M.D. published "Peptide Inhibition of the P-K Reaction" based on blocking up to 89% of the IgE receptors on mast cells by the pentapeptide representing amino acids 320 to 324 on the epsilon chain of IgE. Confirming the IgE binding site, in 1979 he published in Immunology "Inhibition of IgE binding to tissue culture cells and leucocytes by pentapeptide" (ref).

External links